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Short-Course Montelukast for Intermittent Asthma in Children

A Randomized Controlled Trial

¹ Respiratory Medicine, Royal Children's Hospital, Melbourne, Australia; ² General Practice and Primary Care, University of Aberdeen, Aberdeen, United Kingdom; ³ Women's and Children's Health, University of NSW, Sydney, Australia; ⁴ Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia; ⁵ Medical School, Australian National University, Canberra, Australia; and ⁶ Merck, Sharp, & Dohme (Australia) Pty. Ltd., Sydney, Australia

Correspondence and requests for reprints should be addressed to Prof. Colin F. Robertson, M.D., F.R.C.P., Department of Respiratory Medicine, Royal Children's Hospital, Parkville, Victoria 3052 Australia. E-mail: colin.robertson{at}rch.org.au

	ABSTRACT

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Rationale: In children, intermittent asthma is the most common pattern and is responsible for the majority of exacerbations. Montelukast has a rapid onset of action and may be effective if used intermittently.

Objectives: To determine whether a short course of montelukast in children with intermittent asthma would modify the severity of an asthma episode.

Methods: Children, aged 2–14 years with intermittent asthma participated in this multicenter, randomized, double-blind, placebo-controlled clinical trial over a 12-month period. Treatment with montelukast or placebo was initiated by parents at the onset of each upper respiratory tract infection or asthma symptoms and continued for a minimum of 7 days or until symptoms had resolved for 48 hours.

Measurements and Main Results: A total of 220 children were randomized, 107 to montelukast and 113 to placebo. There were 681 treated episodes (345 montelukast, 336 placebo) provided by 202 patients. The montelukast group had 163 unscheduled health care resource utilizations for asthma compared with 228 in the placebo group (odds ratio, 0.65; 95% confidence interval, 0.47–0.89). There was a nonsignificant reduction in specialist attendances and hospitalizations, duration of episode, and -agonist and prednisolone use. Symptoms were reduced by 14% and nights awakened by 8.6% (p = 0.043), and days off from school or childcare by 37% and parent time off from work by 33% (p < 0.0001 for both).

Conclusions: A short course of montelukast, introduced at the first signs of an asthma episode, results in a modest reduction in acute health care resource utilization, symptoms, time off from school, and parental time off from work in children with intermittent asthma.

Key Words: asthma • montelukast • pediatric

AT A GLANCE COMMENTARY TOP ABSTRACT AT A GLANCE COMMENTARY METHODS RESULTS DISCUSSION REFERENCES   Scientific Knowledge on the Subject Intermittent asthma is the most common pattern of asthma in children and is responsible for the majority of hospital admissions. Montelukast has a rapid onset of action and may be effective if used intermittently. What This Study Adds to the Field A short course of montelukast, introduced at the first signs of an asthma episode, results in a modest reduction in acute health care resource utilization, asthma symptoms, and school and parental work absence in children with intermittent asthma.

 

Intermittent asthma, described as isolated episodes with an asymptomatic interval (1), is the most common pattern of childhood asthma, accounting for up to 75% of children with asthma (2). Episodes are commonly triggered by viral respiratory infections (3, 4) and the more severe episodes account for the majority of pediatric emergency department attendances (5) and hospital admissions for asthma (6). Although episodic high-dose inhaled corticosteroids (ICS) modify the severity of acute episodes in children, the regular use of low-dose ICS in children with intermittent asthma does not reduce the frequency or severity of the episodes (7). Current treatment recommendations suggest the intermittent use of inhaled bronchodilators and oral prednisolone for management of acute episodes (8). Recent evidence has challenged the benefit of parent-initiated prednisolone in young children with repeated virus-associated wheeze (9). Acute episodes of asthma in young children place a significant burden on health resources. Admissions to hospital for asthma for children aged 0 to 4 years are five times more common and for those aged 5 to 14 years are twice as common when compared with adults (10). A similar pattern is seen for emergency department attendances and general practitioner visits (10).

Montelukast sodium is a specific leukotriene receptor antagonist that has been shown to be effective in children with mild, persistent asthma (11) and is currently recommended as a preventative agent for this group of children (1, 8). Clinical trials of montelukast in children and adults have demonstrated that the maximum clinical benefit is achieved within the first 24 hours (12–14). The rapid onset of clinical benefit from montelukast suggested the novel approach of introducing a short course of montelukast, at the first signs of an upper respiratory tract infection (URTI) or asthma symptoms, to modify the severity of an acute episode of asthma. Some of the results of this study have been previously reported in the form of an abstract (15, 16).

	METHODS

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Aim
The objective of the study was to determine the efficacy of a parent-initiated short course of montelukast in children with intermittent asthma.

Patients
Eligibility criteria were as follows: age 2 to 14 years, a history of doctor-diagnosed intermittent asthma, asymptomatic between episodes, and no asthma medication between episodes. Children were required to have a history of at least three, but no more than six, episodes within the previous 12 months requiring either a hospital admission, an emergency department visit plus two general practitioner (GP) visits during asthma exacerbations, or three or more GP visits during asthma exacerbations.

Procedures
This was a multicenter, double-blind, randomized, placebo-controlled trial. The dose of montelukast for children aged 2 to 5 years was 4 mg and for those aged 6 to 14 years, 5 mg. The parent/caregiver was issued with study medication to commence at the onset of asthma symptoms or the first sign of an URTI in those children in whom an URTI was usually followed by asthma. Treatment was given at bedtime for a minimum of 7 days or until symptoms had resolved for 48 hours up to a maximum of 20 days.

Patients could receive inhaled -agonist and oral prednisolone according to a customized asthma management plan. Two weeks after completion of the episode, the study team reviewed the patient and issued another course of the same medication for management of a subsequent episode. The patient could be treated for up to five episodes within the 12-month period.

The study was approved by the Human Research Ethics Committees of each participating center, and written, informed consent was obtained from the parent or guardian.

Endpoints and Definitions
The primary outcome measure was the total unscheduled acute health care resource utilization (HRU) specific for asthma, which included unscheduled visits to a GP, a specialist pediatrician, an emergency department, and admission to hospital. Secondary endpoints included the individual components of unscheduled HRU for asthma, duration of episode, total daily symptom score, -agonist use, oral prednisolone use, parent/caregiver days lost from work, number of nights the patient had disturbed sleep, and patient days absent from school or childcare. A symptom diary was completed by parents/caregivers (17). The duration of episodes was defined as the days from start of symptoms to no -agonist use, asthma, or URTI symptoms. Atopy was defined as a history of eczema or hay fever.

Statistical Analysis
The principal analyses were intention-to-treat analyses, but sensitivity analyses and a per protocol analysis were also done on the primary endpoint. Between-group comparisons of categorical data were assessed using the chi-square test. Between-group comparisons for continuous data were made using the nonparametric Mann-Whitney test, and hence medians and interquartile ranges (IQRs) are reported. The treatment effect on total number of HRUs was examined using Poisson regression. The model was adjusted for clustering of multiple episodes per patient, length of time in study (which was log transformed and used as the offset variable), and rhinitis history.

Differences between treatment groups for proportions of episodes with at least one HRU or other secondary endpoints were analyzed using logistic regression and reported as odds ratios (ORs), with 95% confidence intervals (CIs). For comparative purposes, the logistic models were performed in two stages: (1) unadjusted and (2) adjusted for clustering by patient, (log) duration in study, and rhinitis history.

A limited cost consequence analysis was also conducted.

	RESULTS

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A total of 236 patients were recruited, 220 patients were randomized into two treatment groups and 202 patients received at least one dose of study medication (Figure 1). Recruitment commenced in June 2000 and follow-up completed in February 2003. The baseline characteristics of the patients are described in Table 1. There was a greater proportion of patients with history of rhinitis and atopic dermatitis in the montelukast group. There were no significant differences between the two treatment groups for all other baseline characteristics. Of the 202 randomized patients receiving at least one dose of study medication (97 montelukast, 105 placebo), all were included in the intention-to-treat analysis for their study duration. The mean duration of the study period was 307 days for the montelukast group and 284 days for the placebo group. There were 345 episodes treated with montelukast and 336 treated with placebo.

View larger version (21K): [in this window] [in a new window]   Figure 1. Consort diagram showing flow of subjects through the study.

Secondary Endpoints
The utilization of individual health care resources is presented in Tables 2 and 3. In Table 2, the results are expressed as a proportion of the treated episodes that utilized individual health care resources. Several treated episodes utilized more than one health resource. In Table 3, the total number of individual HRUs during all treated episodes is presented. The difference is most obvious in GP visits and emergency department attendances where there were more multiple attendances in the placebo-treated group.

The symptom scores are reported in Table 4. The total symptom scores for all episodes considered together were statistically significantly lower in the montelukast group (median, 37; IQR, 19–62) compared with the placebo group (median, 43; IQR, 22–73) (p = 0.049). There was no significant difference between groups in the median number of puffs of -agonist used per episode (median of 36 puffs for each group) or oral steroid use (20.5% of episodes in the montelukast group and 24.3% in the placebo group; OR, 0.81; 95% CI, 0.56–1.17; p = 0.25).

View larger version (9K): [in this window] [in a new window]   Figure 2. Subgroup analysis of primary endpoint, proportion of episodes treated that required health resource utilization.

Adverse Events
There was no significant difference in the incidence of adverse events between the two groups (Table 6).

	DISCUSSION

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This study demonstrated that, for children with intermittent asthma who have had clinically significant episodes, a short course of montelukast, initiated by the parent or caregiver results in 28.5% fewer absolute number of HRUs specific for asthma, including clinically significant reductions in GP visits and emergency department attendances. Although there was no significant effect on -agonist or oral prednisolone use, there was a significant reduction in asthma symptoms. Furthermore, treatment with montelukast resulted in a significant reduction in the number of days off from school or childcare for the child and days lost from work for the parent or caregiver. Although the difference in the number of days lost from work between treatment groups was relatively small, the days absent per year is a conservative estimate based on the presumption of a 365-day working year. Nonworking carers were asked to estimate likely time off work. Although there were more children with a history of atopy in the active treatment group, atopy did not influence the treatment effect.

Epidemiologic studies have detected viral URTIs in 85% of childhood asthma exacerbations (3, 4). Cysteinyl leukotrienes are released during infection with respiratory syncytial virus in infants (18) and in virus-associated wheeze in preschool children (19). Cysteinyl leukotrienes appear to mediate abnormalities of lung function, including mucus production, decreased mucociliary clearance, changes in vascular permeability, and smooth muscle contraction (20). Montelukast is an oral specific cysteinyl leukotriene (CysLT1) receptor antagonist with bronchoprotective effects for 20 to 24 hours after dosing (21). In persistent asthma, montelukast has a rapid onset of action with significant benefits demonstrated within 24 hours (12–14). In acute asthma, significant bronchodilatation has been demonstrated within 10 minutes after intravenous administration of montelukast (22). The rapid onset of action, together with an excellent safety profile, provides a sound rationale for the intermittent use of montelukast for the management of intermittent asthma in children. The clinical benefit could result from either an antiinflammatory effect or bronchodilatation or a combination of both.

Beyond the use of -agonists, the current approaches to management of this pattern of asthma have resulted in little benefit in modifying the course of the illness. The regular use of ICS is not effective (7) and, although the use of systemic steroids in the emergency department is effective in reducing hospitalization (23), benefits from the common practice of parent-initiated therapy have not been demonstrated (9). A recent study examining the effect of regular montelukast therapy on asthma exacerbations in young children with intermittent asthma demonstrated a 31% reduction in the rate of asthma exacerbations and reduction in the overall rate of corticosteroid use of 32% (24). In that study, the children had asthma symptoms on only 24% of days in the montelukast group and on 27% of days in the placebo group. Because children with intermittent asthma are asymptomatic for the majority of the time, the early use of intermittent therapy may provide a clinically and cost-effective alternative approach to management. The current study was designed to evaluate parent-initiated therapy with montelukast in circumstances that are likely to mimic community-based practice. A key component of this study was the impact of asthma on the family, measured by days absent from school, nights of disturbed sleep, and the number of parent days lost from work. Furthermore, the strategy of parent-initiated therapy required children, on average, to take their study drug on only 30 days of the year, rather than 365 days, providing a further cost benefit for the family.

The components of symptom score and -agonist use are more difficult to assess in intermittent asthma because the symptoms of the viral illness that commonly trigger the episode can be readily confused with those of asthma. This is particularly relevant for cough. The lack of effect seen for -agonist use may, in part, be explained by the use of -agonists to relieve the symptom of cough in children with asthma. The use of parent-initiated prednisolone was part of the asthma management plan issued to each parent. Although specific guidelines were provided for its use, parent-initiated prednisolone is widely practiced in Australia and parents have a low threshold to initiate prednisolone during an episode of asthma. For future studies of intermittent asthma in children, it would be important to develop a symptom score that might more clearly distinguish between the symptoms of asthma and those of the associated viral illness. The current study does, however, provide useful information on which to base power calculations for future studies.

In the current literature, the terms "intermittent asthma" and "virus-associated wheeze" are used almost interchangeably. After a detailed survey to determine the spectrum and severity of asthma in children in 1969, Williams and McNicol suggested that asthma and wheezy bronchitis in children shared many characteristics and could be different ends of the same spectrum (25). This concept was reinforced by Speight and colleagues in 1983 who promoted the concept that "all that wheezes is probably asthma" (26). In recent years, there is clear recognition that there are a number of different phenotypes in childhood asthma. Silverman proposed a distinction between virus-associated asthma and persistent asthma (27), but current national and international guidelines continue to refer to intermittent asthma. In this study, we used the term intermittent asthma but recognized that it could be interchanged with virus-associated wheeze. During recruitment and screening, great attention was given to ensuring that, between episodes, the children did not have any symptoms of persistent asthma nor use any asthma medications. The majority of children for this study were recruited after an emergency department attendance for asthma and the remainder were recruited from general practice. In Australia, emergency departments are commonly used for primary care for asthma episodes, and therefore do not necessarily reflect the severity of the episode.

Another approach to assessing the results of this study is the number of episodes needed-to-treat to prevent utilization of a health resource during the episode. Although this usually applies to individual patients, in this study the individual episode was the unit used for analysis. Some episodes had more than one HRU, particularly GP visits and emergency department attendances. For 100 patient episodes treated with montelukast, there would be an avoidance of one hospital admission, six emergency room attendances, two specialist consultations, and eight GP visits.

The idea for the study was conceived by one of the authors (C.F.R.) and an approach made to the pharmaceutical company for funding. The project was funded by Merck, Sharp, & Dohme Australia. A steering committee of peers was established to develop a protocol independent of the sponsoring company. The company facilitated the project and fully funded it. The company was responsible for supply of drug, placebo, and other materials. Members of the PRE-EMPT Study Group were investigators at each center. Data management, analysis of the data and production of the internal study report, and preparation of the manuscript were performed independently of the sponsor. The aim of the study was to assess efficacy of a prescribed short course of montelukast compared with placebo. The prestudy analysis plan was based on the premise that only children who actually received study medication would be considered for analyses. The denominator throughout all analyses was total number of asthma episodes, and analyses were based on what proportion of the resultant episodes required some form of HRU, incurred parental days off work, child's lost sleep, and so forth. Eighteen children did not receive any medication nor did they report any episodes, and so, by definition, they had to be excluded for all univariate tests and Poisson regression models. The choice of a 7-day minimum course of study drug was a practical decision. It was believed that, from previous clinical experience, the duration of therapy for the majority of the episodes would be less than 7 days. Rather than have yet another period, which would compound the analysis, and to make it clearer for the parents, it was decided to have a fixed 7-day minimum with a possible extension if necessary.

In summary, for children with intermittent asthma, a course of parent-initiated montelukast at the onset of an URTI or asthma symptoms results in a modest reduction in HRU symptoms, parent time lost from work, and absence from school or childcare.

	FOOTNOTES

 
Supported by Merck, Sharp, & Dohme (Australia) Pty. Ltd.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200510-1546OC on November 16, 2006

Conflict of Interest Statement: C.F.R. has been a member of advisory boards and has received lecture fees and educational grants from Merck, Sharp, & Dohme (MSD) and AstraZeneca (AZ) and has received a consultancy fee from MSD. D.P. has received honoraria for speaking at sponsored meetings from the following companies: Altana and MSD. He has received honoraria for advisory panels with Altana, GlaxoSmithKline (GSK), MSD, and Novartis. He or his research team have received funding in the last 3 years for research projects from 3M, Altana, AZ, Boehringer-Ingelheim (BI), GSK, IVAX Corp., and MSD. He has received support to attend respiratory conferences from Altana, AZ, GSK, and MSD. He received funding ($9,500) through the independent research company Thorpe Respiratory Research to undertake the analysis of the study. R.H. participated as a speaker in a pharmaceutical company–sponsored satellite symposium at an international conference (GSK), and at a local course (AZ), and received research grant funding of $52,000 from Pharmaxis, Ltd, and $11,500 from MSD (both in 2004) for participating in multicenter trials. C.M. serves on advisory boards for MSD, GSK, and Altana Pharma. N.G. did not personally receive any income from MSD for the conduct of this trial. The Academic Unit he worked for was reimbursed for costs associated with conduct of the trial. D.F. has been a member of the Australian Singulair Advisory Board for the last 3 years (2003, $4,500; 2004, $3,000; 2005, $1,500) and received lecture fees in 2005 ($1,000) from MSD Australia. He has participated as a speaker at meetings financed by GSK, AZ, and MSD in the last 3 years. A.J.L. has received payments of £2,735 from Thorpe Respiratory Research to undertake the statistical analysis of this study, as well as £15,000 from Altana in 2005 and £6,000 from Schering Plough in 2006 for statistical analyses of specific research projects. J.T. has been an employee of MSD (Australia) Pty Ltd since 1995 and currently holds stock options in Merck and Co. M.S. was employed by MSD for the period March 1992 to February 2004 and currently holds 1,000 stock (shares) in the same company.

The PRE-EMPT Study Group:Nicholas Freezer, David Armstrong: Monash Medical Centre, VIC; Paul Francis, Claire Wainwright: Royal Children's Hospital, QLD; Hugh Allen: Royal North Shore Hospital, NSW; Nigel Dore: Wesley Medical Centre, QLD; Peter LeSouef: Princess Margaret Hospital for Children, WA; Michael Smiley: Lyell McEwin Health Service, SA; Colin Robertson: Royal Children's Hospital, VIC; Craig Mellis, Dominic Fitzgerald: The Children's Hospital at Westmead, NSW; Richard Henry: Sydney Children's Hospital, NSW; Nicholas Glasgow, Tim McDonald, Kam Sinn: The Canberra Hospital, ACT; Alan James: Wollongong Hospital, NSW; David Lines: Flinders Medical Centre, SA; Ian Charlton: NSW; Leon Goldstein: NSW.

Received in original form October 2, 2005; accepted in final form November 16, 2006

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TOP ABSTRACT AT A GLANCE COMMENTARY METHODS RESULTS DISCUSSION REFERENCES

 

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This Article Abstract Full Text (PDF) Online Supplement All Versions of this Article: 200510-1546OCv1 175/4/323    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Robertson, C. F. Articles by Sant, M. Search for Related Content PubMed PubMed Citation Articles by Robertson, C. F. Articles by Sant, M.